Methyl 2-[(1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)ethylidene]-1,3,3-trimethylindoline-5-carboxylate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

other information

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

There are no experimental toxicokinetic data available for the substance and this statement is based on available data as physico-chemical data and toxicological data. This assumption was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

GLP compliance:

no

Available physico-chemical information taken into account:

Physical state:

The substance is a solid red powder

Structure:

Identification: Macrolex Orange R

CAS Number: 5718-26-3

Chemical Name: 1H-Indole-5-carboxylic acid, 2-[2-(1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)ethylidene]-2,3-dihydro-1,3,3-trimethyl-, methyl ester

Molecular weight: C25H25N3O3: 415 g/mol

Water solubility:

low solublility: 0.44 mg/L

Log Pow:

log Pow = 3.6 at a pH value of 7.2.

Vapor pressure:

Low: 7.78E-10 Pa at 25 °C.

General considerations:

In general, log Kow values between 1 and 4 and molecular weight below 500 are favourable for absorption regarding oral/GI absorption, respiratory absorption and dermal absorption. Low water solubility of 0.44 mg/L might limit absorption. No information of metabolic transformation of Macrolex Orange R is available.

Estimation of oral absorption:

In the acute oral study 5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item. No symptoms or mortality were observed. Consequently the discriminating dose is 5000 mg/kg (highest dose tested).

The oral (gavage) administration of Macrolex Orange R to rats, for twenty-eight days at dose levels of 250, 500 or 1000 mg/kg bw/day was well tolerated and did not result in any toxicologically significant effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was 1000 mg/kg bw/day (highest dose tested) within the confines of this study type.

Overall: Molecular weight and logP values are in the range of compounds absorbed after oral dosing. Based on the low water solubility an absorption following ingestion is not likely. This is supported by toxicological data after oral dosing. No toxicologically relevant effects were seen after acute or 28 days exposure. In conclusion, it is likely that oral absorption is low.

Estimation of dermal absorption:

There are no dermal studies available; the substance is not irritating to the skin or eyes. Based on the low water solubility low absorption after dermal contact is assumed.

Estimation of absorption via inhalation:

A study on the acute inhalation toxicity of Macrolex Orange R on rats has been conducted in accordance with OECD Test Guideline no. 403 (2009). The reparability of the aerosol was adequate and in compliance with the test guidelines [the mass median aerodynamic diameter (MMAD) was 3.70 µm, the geometric standard deviation (GSD) was 2.14]. Rats exposed to the test item did not show clinical signs at 2441 mg/m³. During the clinical observation test item-dependent orange discoloration was seen on nose and muzzle as well as on the head and forelegs. No findings were seen at the functional observation battery. No toxicological relevant test item-related changes in incremental body weight gain were observed. Significantly decreased body temperatures were found in animals exposed to 2441 mg/m³ test item when compared to the control animals. Mortality did not occur at 2441 mg/m³. No gross-pathological findings were observed at necropsy in animals exposed to 2441 mg/m³ Macrolex Orange R.

Based on the physicochemical parameters and the absence of effects in an acute inhalation study it is assumed that the absorption via inhalation is low.

Estimation of distribution:

Based on the low water solubility it is not assumed that the substance distributes into cells.

Estimation of accumulation:

In general substances with high log P values have long biological half-lives. Substances with log P values of 3 and less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may be accumulate if exposures are continuous.

Based on the log P of 3.6, accumulation of Bayscript Magenta BB is unlikely.

Estimation of metabolism:

In vitro genotoxicity data do not indicate any genotoxic metabolites. The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay), the MNT (in vitro mammalian cell Micronucleus Test) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene))

Estimation of excretion:

Characteristics favorable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Based on the physicochemical data an excretion of via feces is assumed.

Executive summary:

Estimation of oral absorption:

Molecular weight and logP values are in the range of compounds absorbed after oral dosing. Based on the low water solubility an absorption following ingestion is not likely. This is supported by toxicological data after oral dosing. No toxicologically relevant effects were seen after acute or 28 days exposure. In conclusion, it is likely that oral absorption is low.

Estimation of dermal absorption:

There are no dermal studies available; the substance is not irritating to the skin or eyes. Based on the low water solubility low absorption after dermal contact is assumed.

Estimation of absorption via inhalation:

Based on the physicochemical parameters and the absence of effects in an acute inhalation study it is assumed that the absorption via inhalation is low.

Estimation of distribution:

Based on the low water solubility it is not assumed that the substance distributes into cells.

Estimation of accumulation:

In general substances with high log P values have long biological half-lives. Substances with log P values of 3 and less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may be accumulate if exposures are continuous.

Based on the log P of 3.6, accumulation is unlikely.

Estimation of metabolism:

In vitro genotoxicity data do not indicate any genotoxic metabolites. The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay), the MNT (in vitro mammalian cell Micronucleus Test) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene))

Estimation of excretion:

Characteristics favorable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Based on the physicochemical data an excretion of via feces is assumed.

Description of key information

Estimation of oral absorption:

Molecular weight and logP values are in the range of compounds absorbed after oral dosing. Based on the low water solubility an absorption following ingestion is not likely. This is supported by toxicological data after oral dosing. No toxicologically relevant effects were seen after acute or 28 days exposure. In conclusion, it is likely that oral absorption is low.

Estimation of dermal absorption:

There are no dermal studies available; the substance is not irritating to the skin or eyes. Based on the low water solubility low absorption after dermal contact is assumed.

Estimation of absorption via inhalation:

Based on the physicochemical parameters and the absence of effects in an acute inhalation study it is assumed that the absorption via inhalation is low.

Estimation of distribution:

Based on the low water solubility it is not assumed that the substance distributes into cells.

Estimation of accumulation:

In general substances with high log P values have long biological half-lives. Substances with log P values of 3 and less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may be accumulate if exposures are continuous.

Based on the log P of 3.6, accumulation is unlikely.

Estimation of metabolism:

In vitro genotoxicity data do not indicate any genotoxic metabolites. The substance is negative in the absence and in the presence of S9 extracts (Ames test (Bacterial Reverse Mutation Assay), the MNT (in vitro mammalian cell Micronucleus Test) and the HPRT test (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene))

Estimation of excretion:

Characteristics favorable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Based on the physicochemical data an excretion of via feces is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential